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HyperDSC and DMA Allow Greater Detection of Amorphous Materials
by Kevin P. Menard, Product Manager, and Peng Ye, Applications Specialist, PerkinElmer LAS
Thermal analysis has long been a tool in the pharmaceutical laboratory, but its usefulness has often been limited by the weakness of the transitions of interest. For example, the ability to detect low levels of amorphous materials is of great interest whether as a screening tool for solubility and stability studies or for estimation of the collapse temperature of protein-excipient cakes in lyophilization. However, the low energy of these events, especially as the concentration of these materials decreases, often means detecting them is difficult in differential scanning calorimetry (DSC). Generally speaking, DSC is not able to detect the amorphous content at less than 10%. Due to the physical form of these types of samples being powdery, using a more sensitive technique such as dynamic mechanical analysis (DMA) has not been possible.
The recent development of high scanning rate DSC has greatly increased the ability of DSC to detect weak transitions. Parallel with this, developments in sample handling for the DMA, such as the material pocket, have allowed this technique to be applied to materials previously considered too fragile or unsuitable for mechanical analysis.
HyperDSC Techniques
Pioneered on plastics by Mathot1 and Piper2, HyperDSC exploits the small furnace mass of power compensation DSCs to scan at rates of over 100 C/minute, covering a broad temperature range. Peak height in the DSC is a function of scanning rate, and increasing the rate to 300 to 500 C/minute increases peak height dramatically. Fast scanning rate also means shorter experiment time and high efficiency, which improves the sample throughput in the pharmaceutical lab dramatically.
Figure 1. Amorphous lactose by Hyper DSC.Click to enlarge. |
Improvements in instrumentation allow data collected at these rates to be quantitative, and this allows the detection of transitions that were previously too weak to be determined. Because the step change of glass transition is proportional to the amorphous content, quantifying the amorphous content is possible.3 The high sensitivity of HyperDSC enables the use of very small amounts of sample. The actual low level of amorphous content in real formula can now be detected using HyperDSC.4
Even when it is claimed to be purely crystalline, lactose contains small levels of amorphous material. Normally this is at concentrations too low to be seen by DSC. However, as seen in Figure 1, very low levels of lactose can be detected at high scanning rates.
Dynamic Mechanical Analysis on Powders
The development of the material pocket has enabled powdered materials to be investigated in DMA. The size of the observed glass transition in the tan-d response is directly proportional to the amount of amorphous material in the sample. As the crystalline component has no glass transition, it has no contribution to the result obtained.
DMA works by applying an oscillating force to the material, and the resultant displacement of the sample is measured. From this, the stiffness can be determined and tan d can be calculated. Tan d is the ratio of the loss component to the storage component. By measuring the phase lag in the displacement compared to the applied force, determining the damping properties of the material is possible. Tan d is plotted against temperature and glass transition and is normally observed as a peak because the material will absorb energy as it passes through the glass transition.
Figure 2. Crystalline and amorphous lactose samples. Click to enlarge. |
Lactose is a very important pharmaceutical excipient used in tablets and inhalation products. It is prone to forming amorphous regions upon processing, however, and can be problematical to characterize the exact amount of amorphous material in a sample. Figure 2 illustrates a typical DMA response from both a fully crystalline and a fully amorphous sample of lactose. The amorphous sample shows various regions of interest in the tan d corresponding to loss of water, the glass transition, crystallization of the amorphous material, loss of hydrated water and finally melting. The crystalline material has no peak corresponding to the initial loss of water as it is significantly less hygroscopic and contains less latent water. It obviously has no glass transition because of the lack of any amorphous material presence. The latter peaks correspond to the loss of hydration water and then melting.
The peak of main interest is the glass transition, which exclusively represents the amorphous material in the sample. The magnitude of tan d, as stated previously, is proportional to the amount of amorphous material in the sample. After mass and baseline corrections, the data can be plotted against amorphous content of known samples to achieve a calibration curve. Figure 3 illustrates a plot of relaxation strength—defined as 1 minus the glass transition peak value of the tan d—against amorphous content. The calibration curve shows a good correlation of fit. This example takes into account that the technique has a theoretical limit of detection of 2.8% w/w for amorphous lactose, and the method is comparative to other techniques that have been used to quantitate amorphous lactose5. Other amorphous materials including protein excipient mixtures6 and drugs7 have been studied also.
Figure 3. Relaxation strength versus amorphous content.Click to enlarge. |
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Figure 4. Three different molecular weights of PEG.Click to enlarge. |
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Material pockets are not limited to just looking at amorphous material. Figure 4 shows the tan-d response for the three polyethylene glycol (PEG) samples investigated. All data shown was analyzed at 1-Hz frequency. The glass transition is shown to be a strong event in all samples, and a clear trend of increasing Tg with decreasing molecular weight is evident. The samples of PEG4000 and PEG6000 are almost overlapping, which indicates these materials are similar in properties due to the close molecular weights. The other material having a molecular weight of 20,000 is different. The melting point increases with increasing molecular weight. Larger differences seen in the melting points are due to the larger differences in lattice energy between the three samples.
Figure 5. Sucrose by DMA.Click to enlarge. |
DMA is much more adaptable to environmental changes than other techniques, and the combination of the material pockets with a humidity generator provides a powerful tool for working with excipients. Figure 5 shows sucrose run at three relative humidities—a test that may be impossible to run except in a DMA using the material pockets and humidity generator. Sample A was very dry and shows the Tg at the highest temperature. Exposed to a modest amount of water, Sample B shows a small reduction in the Tg, and Sample C was run while exposed to 50% relative humidity in the DMA 8000.
Hyper DSC and DMA represent new tools for the pharmaceutical laboratory, expanding its abilities to handle the newer and more difficult materials in use today.
References
1. Mathot, V. et al. 2002. High-speed calorimetry for the study of the kinetics of (de)vitrification, crystallization, and melting of macromolecules. Macromolecules 35: 3601.
2. Piper, T. et al. 2006. Improving and speeding up the characterization of substances, materials, and products: Benefits and potentials of high speed DSC. American Labs 38: 21-25.
3. Saunders, Mark et al. 2004. The potential of high speed DSC (Hyper-DSC) for the detection and quantification of small amounts of amorphous
content in predominantly crystalline samples. International Journal of Pharmaceutics 274: 35-40.
4. Buckton, G. et al. 2006. HyperDSC studies of amorphous polyvinylpyrrolidone in a model wet granulation system. International Journal of Pharmaceutics 312: 61-65.
5. Royall, P. et al. 2005. The development of DMA for the detection of amorphous content in pharmaceutical powdered materials. International Journal of Pharmaceutics 301: 181-191.
6. Carpenter, J., K. Menard et al. 2007. Characterization of amorphous materials and lyophilized protein excipient mixtures by HyperDSC and DMA. Lecture presented at the NATAS Conference, August 26-29, in East Lansing, Michigan.
7. Gupta, P. and Arvind K. Bansal 2005. Devitrification of amorphous celecoxib. AAPS PharmSciTech
6(2): E223-E230.
For more information, contact Kevin Menard, product manager, Mechanical Analysis, PerkinElmer, at Kevin.Menard@perkinelmer.com or by phone at 800-762-4000.
At A Glance
• Generally speaking, DSC is not able to detect the amorphous content at less than 10%
• The high sensitivity of HyperDSC enables the use of very small amounts of sample
• The development of the material pocket has enabled powdered materials to be investigated in dynamic mechanical analysis (DMA)
• Combining the material pockets with a humidity
generator provides a powerful tool for working with excipients
Online
For additional information on methods discussed in this article, see Laboratory Equipment magazine online at www.LaboratoryEquipment.com or the following Web site:
• www.perkinelmer.com
Laboratory Equipment
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